Dengue fever is one of the most important emerging infections across the globe. The goal of this project is to characterize the transcriptional responses of children with dengue fever. The broad objectives are to identify critical features of the protective and pathogenic features of the host response, and to provide a basis for developing novel diagnostic and prognostic tools in humans with dengue fever and other similar illnesses. There are three Specific Aims: Aim i. Characterization of the relationship between transcriptional response and disease evolution in dengue infection. Genome-wide transcript abundance levels will be measured in peripheral blood mononuclear cell (PBMC) samples collected from children diagnosed with dengue fever in Managua, Nicaragua. We will evaluate the clinical and laboratory features associated with inter-individual variation in gene expression, and determine the relationship between transcriptional profiles and WHO staging criteria. Analysis of sequential samples will provide important information about the relative stability of clinically relevant expression signatures, and help to identify temporal trends in associated biological processes. Aim 2. Identification of a gene set for predicting Dengue Hemorrhagic Fever/Dengue Shock Syndrome. The ability to distinguish children destined to develop DHF/DSS from those who are destined to have a benign course of infection is a critical unmet clinical need. We will identify a set of genes whose corresponding transcript abundance pattern predicts the clinical evolution of acute dengue infection. An important feature of this work will be the use of samples collected over a separate dengue season as an independent test set for validation. Aim 3. Classification of dengue fever and dengue-like illnesses using transcription profiles. Genome-wide transcript abundance will be measured in patients who are evaluated for dengue fever because of similarities in clinical presentation, but are found not to have dengue. Comparison of expression profiles from those with and without dengue will lead to the identification of host response features that are dengue-specific, and those that are conserved among many infections. This work will identify markers that can be used to improve the diagnosis of dengue fever and other diseases that mimic dengue.

Public Health Relevance

Dengue fever (DF) and its dreaded complications, Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), have become the most important mosquito-borne viral diseases in the world. Unfortunately, we do not adequately understand the disease mechanisms, and are unable to predict during the early phase of the illness?when interventions are most effective?which patients are destined to develop DHF/DSS. The proposed work will lead to novel diagnostic and prognostic tools, and an improved understanding of this disease, with the goal of managing patients more effectively.